Specific learning disabilities are the most common neurological complication in children with neurofibromatosis type I (NF1), a disorder affecting 1/4000 people world-wide. This genetic disease is caused by mutations in the NF1 gene which encodes neurofibromin, a Ras GTPase activating protein that is highly expressed in the brain. Our studies of mice mutant for the neurofibromin gene (Nf1+/- ) indicated that these mutants showed enhanced GABAA-mediated inhibition, deficits in long-term potentiation (LTP) and in spatial learning. In this application we propose to test the hypotheses that the spatial learning deficits of mice with an heterozygous-null germ-line Nf1 mutation (Nf1+/- mice), that model closely the human condition, are due to enhanced inhibition (either because of pre- or post-synaptic changes) that leads to deficits in LTP and subsequently to abnormalities in learning. We propose to pin-point both the cellular mechanism by which the Nf1+/- mutation affects inhibition, plasticity and learning and the brain region(s) affected by this mutation. To accomplish this we will use transgenic mice with cell-type (inhibitory or excitatory neurons) restricted deletions of Nf1, Adeno-Associated Virus type 2 Cre-recombinase (AAV-Cre) driven and region-specific (hippocampus, prefrontal cortex) deletions of Nf1, as well as a number of pharmacological, electrophysiological and behavioral tools. The specific aims of this proposal are: SPECIFIC AIM #1 - To determine whether deletions of Nf1 in either hippocampus or prefrontal cortex can account for the learning deficits of the Nf1 mutant mice. SPECIFIC AIM #2- To determine the critical cellular locus for neurofibromin's role in learning and memory. SPECIFIC AIM #3 - To determine how neurofibromin affects GABA-mediated inhibition and LTP. Although there is a great deal of data that implicate Ras/MAPK signaling in plasticity and learning, it is still unclear how this signaling pathway modulates these complex processes. The studies proposed here will further our understanding of the role of neurofibromin/Ras/MAPK signaling in the modulation of GABA-mediated inhibition, LTP and learning. Importantly, they will also be crucial for developing targeted treatments for the debilitating learning disabilities associated with Neurofibromatosis Type I.